title: NADPH oxidase subunit p22(phox)-mediated reactive oxygen species contribute to angiogenesis and tumor growth through AKT and ERK1/2 signaling pathways in prostate cancer.
abstract: Excessive generation of reactive oxygen species (ROS) in cancer cells is associated with cancer development, but the underlying mechanisms and therapeutic significance remain elusive. In this study, we reported that levels of ROS and p22(phox) expression are greatly increased in human prostate cancer tissues, and knockdown of p22(phox) by specific small interfering RNA (siRNA) decreased ROS levels in prostate cancer cells. We also showed that stable downregulation of p22(phox) in prostate cancer cells inhibited cell proliferation and colony formation, which was mediated by AKT and extracellular signal-regulated kinase (ERK)1/2 signaling pathways and their downstream molecules hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF). The NADPH oxidase subunit NOX1 was also elevated in prostate cancer cells, and was involved in activation of AKT/ERK/HIF-1/VEGF pathway and regulation of cell proliferation. Knockdown of p22(phox) resulted in inhibition of tumor angiogenesis and tumor growth in nude mice. These findings reveal a new function of p22(phox) in tumor angiogenesis and tumor growth, and suggest that p22(phox) is a potential novel target for prostate cancer treatment.
authors.affiliation: State Key Lab of Reproductive Medicine, and Department of Pathology, Cancer Center, Nanjing Medical, Nanjing 210029, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Urology and Pathology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an 223300, China.
authors.forename: Guang-Bo
authors.initials: GB
authors.lastname: Fu
authors.affiliation: State Key Lab of Reproductive Medicine, and Department of Pathology, Cancer Center, Nanjing Medical, Nanjing 210029, China.
authors.forename: Ji-Tai
authors.initials: JT
authors.lastname: Zheng
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Urology and Pathology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an 223300, China.
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Niu
authors.affiliation: State Key Lab of Reproductive Medicine, and Department of Pathology, Cancer Center, Nanjing Medical, Nanjing 210029, China.
authors.forename: Qiu-Dan
authors.initials: QD
authors.lastname: Chen
authors.affiliation: State Key Lab of Reproductive Medicine, and Department of Pathology, Cancer Center, Nanjing Medical, Nanjing 210029, China; Department of Pathology, Anhui Medical University, Hefei 230032, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yin
authors.affiliation: State Key Lab of Reproductive Medicine, and Department of Pathology, Cancer Center, Nanjing Medical, Nanjing 210029, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Qian
authors.affiliation: State Key Lab of Reproductive Medicine, and Department of Pathology, Cancer Center, Nanjing Medical, Nanjing 210029, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xu
authors.affiliation: State Key Lab of Reproductive Medicine, and Department of Pathology, Cancer Center, Nanjing Medical, Nanjing 210029, China.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Urology and Pathology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an 223300, China.
authors.forename: An-Fang
authors.initials: AF
authors.lastname: Sun
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Yongqian
authors.initials: Y
authors.lastname: Shu
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Hallgeir
authors.initials: H
authors.lastname: Rui
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Ling-Zhi
authors.initials: LZ
authors.lastname: Liu
authors.affiliation: State Key Lab of Reproductive Medicine, and Department of Pathology, Cancer Center, Nanjing Medical, Nanjing 210029, China; Department of Pathology, Anatomy and Cell Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: binghjiang@yahoo.com.
authors.forename: Bing-Hua
authors.initials: BH
authors.lastname: Jiang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D055785:Gene Knockdown Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008819:Mice, Nude; D019255:NADPH Oxidases / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000201:enzymology* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014410:Tumor Stem Cell Assay; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D019255:NADPH Oxidases; C086986:CYBA protein, human; D051057:Proto-Oncogene Proteins c-akt
keywords: 5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate; Angiogenesis; CCK-8; CM-H2DCFDA; Cell Counting Kit-8; DHE; FBS; HIF-1α; MVD; Prostate cancer; ROS; Tumor growth; VEGF; dihydroethidium; fetal bovine serum; hypoxia-inducible factor 1α; microvessel density; p22(phox); reactive oxygen species; vascular endothelial growth factor